Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
  • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
  • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D223/08—Oxygen atoms
  • C07D223/10—Oxygen atoms attached in position 2

Definitions

• the present invention relates to a method for producing an azacycloalkane derivative which is useful as a compound having an absorption promoting action in the field of medicine and aba drug.
• Azacycloalkane derivatives increase the permeability and permeability of drugs, and are stimulants for biological membranes and as absorption enhancers with low overall toxicity. It is a useful compound. Among them, 11- [2— (decinolecho) ethyl] azacyclopentan-12-on has a great effect, and is used for pharmaceuticals and agricultural chemicals. It is expected to be useful.
• Azacycloa Norecan 1—on and excess dihalogen A compound obtained by reacting a non-alkyl with a hydrogenation metal catalyst and a halogenoalkyl are converted to sodium sulfide in the presence of a correlated transfer catalyst.
• the method (3) is a relatively simple method, but a dialkyl disulfide having a boiling point similar to that of the azacycloalkane derivative can be obtained.
• By-products and simple operations such as distillation make it difficult to obtain high-purity products that can be used for pharmaceuticals and agricultural chemicals (see Comparative Example 1 below).
• distillation must be performed after complicated operations such as column chromatography or recrystallization, which is not economically advantageous. No. It has also been confirmed that isomers are generated when benzenes are used as a reaction solvent, and this isomer is subjected to column chromatography, recrystallization, and recrystallization. In addition, it is impossible to remove all by operation such as distillation or the like, resulting in a decrease in purity.
• the present invention has been made to solve the problems of the prior art.
• the present invention provides a method for producing an industrially useful azacycloalkane derivative, which can easily obtain a high-purity target substance and is excellent in economy and workability. Aim to provide ⁇ 92 07 7
• the present inventors have conducted intensive studies to solve the problems as described above, and as a result, have found that 1- (n-anole keninole) azacycloalkane-12-on and alkyne After a radical reaction with rumenole carbane, it is treated with a reducing agent to reduce the by-product guanolequinone sulfide. High-purity azacycloalkane by distillation without the need for column chromatography, etc. They have found that a derivative can be produced, and have completed the present invention.
• the present invention provides:
• n 2 is an integer of 2 to 10
• R is an alkyl group having 3 to 12 carbon atoms
• 1- (n-vinyl) can be used for 1-vinyl-2-on, for example, 1-vinyl-2-pyrrolidone, 1 ⁇ ⁇ 2 ⁇ ⁇ ⁇ ⁇ 1 ⁇ ⁇ 1 ⁇ 1 ⁇ ⁇ — 2 2 ⁇ — 2 2 ⁇ — 2 2 ⁇ — 2 2
• 1-Butenyl lumber to the mouth 2-On etc. are listed o
• the phenolic phenol can be used as propyl melcaptan, butyl melanobutane, pentynole melanobutane, and hexyl melanobutane.
• the ratio of this alkinole-menolecaptan to 11- (n-anolekenyl) azacycloalkane-12-on is 0.8-2.0.
• Radical initiators used here include benzoyl peroxide, acetyl peroxide, tert-butyl peroxide, cumene hydroperoxide, 41 Brombenzen diazodium hydroxide, triphenylene oleoresinol zobenzene, N-nitrosinolenium anilide, 2 , 2'-azobisisobutyronitrile, tetrahydroeninoresuccinonitrile, hydrogen peroxide, etc., preferably benzoyl peroxide, 1, 1 'This is a monolithic bis (butyrol) nitrile.
• the organic solvents include benzene, toluene, xylene, methanol, ethanol, and 11-pro.
• alcohol as an organic solvent, by-products other than zinc phenol, ie, radiazine, can be obtained. Since it is possible to suppress the isomer generated by the cal reaction, the treatment with a reducing agent described later also gives relatively good results.
• This radical reaction is 50 to 150. C, preferably 70 to 12 (0.5 to 20 hours at TC, preferably about 1 to 5 hours).
• the reaction product thus obtained is treated with a reducing agent in a water-containing organic solvent, and further purified by distillation.
• the preservatives used here include metal sulfides such as sodium hydrosulfide and soda sulfide, metals and acids such as tin-zinc, and tris.
• Trinole fins such as methyl phos fins, tri-tin phos fins, tri-propinole phosphines, tri-butin phos fins, etc. Examples include phosphine, phosphonos, triphenylphosphine, soda arsenate, etc., and preferably triphenol phosphine. More preferably, a tributin phosphine is preferably used.
• the amount of the reducing agent used is 0.1 to 50 mol% with respect to 1- (n-alkenyl) azacycloanolecan-12-one. It is preferably between 1 and 15 mol%.
• water-containing organic solvent in this reduction treatment methanol, ethanol, and 1-pro.
• the water content of the water-containing organic solvent is 3 to 50%, preferably 10 to 30%.
• This reduction treatment is performed at 30 (TC or less, preferably in the range of 0 to 100 ° C, more preferably at room temperature (10 to 40 ° C).
• the processing time is 0.5 to 5 hours, preferably about 0.5 to 1.5 hours.
• the radical reaction conditions and the reduction treatment conditions are closely related, and consistent setting of the production conditions is required. For example, if an excess of alkylmercaptan is used to complete the reaction, the amount of reducing agent required for processing will increase accordingly. In order to minimize the generation of dialkyl sulfide, an excess molar amount of 1- (n-vinyl alcohol) azacycloalkane is used. Even in this case, treatment with a reducing agent is necessary, and the amount of the reducing agent can be reduced accordingly.
• 11- (n-vinyl alcohol) -aza-cyclo-al 2 -one and the molar specific force of alkylmercaptan ⁇ also change.
• the reducing agent There is an optimum amount of the reducing agent, and if it is more than that, it is uneconomical, and if it is not, it is not possible to remove dialkyl sulfide. No. That is, in the present invention, the reaction conditions and the processing conditions are closely related, and the effect is exhibited. Since the azacycloalkane derivative obtained by the above method contains almost no by-product dialkyl disulfide, a simple distillation operation was performed. In this way, a high-purity target can be obtained very easily.
• the purity of the obtained substance was 99.4% based on the gas chromatographic area percentage, and did not show any detective resin or sulfide.
• the purity of the obtained substance was 99.3% based on the gas chromatographic area percentage, and no didecyl disulfide was detected.
• the purity of the obtained substance was 99.1% based on the gas chromatographic area percentage, and no didinosyl resulfide was detected.
• the purity of the obtained substance was 99.4% based on the gas chromatographic area percentage, and didecyl disulfide was not detected.
• the purity of the obtained substance was 99.5% based on the gas chromatographic area percentage, and didecyldisanolide was an undetectable force.
• reaction mixture was washed with water, dried, and concentrated under reduced pressure. Then, 50 ml of methanol, 10 parts of water and 0.45 g of tributylphosphine were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 50 ethyl acetate was added to the reaction mixture, washed with water, dried, and the solvent was distilled off under reduced pressure. The obtained oily substance was distilled off to obtain [2- (decinolethio) ethyl] azacid. 17.4 g of clopentan-2-one was obtained.
• the purity of the obtained substance was 99.5% based on the gas chromatographic area percentage, and didesinole resin zolefide was not detected.
• the purity of the obtained substance was 99.0% based on the gas chromatographic area percentage, and did not show any detectable force.
• the purity of the obtained substance was 99.3% based on the gas chromatographic area percentage, and didecinole resin norfide was not detected.
• the purity of the obtained substance is gas chromatographic area percentage This was 99.3%, and did not show any significant difference.
• the purity of the obtained substance was 99.6% based on the gas chromatographic area percentage, and it was found that dioctinoresolefide was not detected.
• the properties, column temperature, and elemental analysis of this substance were measured in the same manner as in Example 1, and were as follows.
• the purity of the obtained substance was 99.1% based on the gas chromatographic area percentage, and no dodecyl disulfoxide was detected.
• the purity of the obtained substance was 99.4% based on the gas chromatographic area percentage, and the dihexyl resin was not detected.
• Table 1 shows the azacycloalkane derivatives obtained in each of the examples, that is, the numbers m and n 2 in the general formula ( ⁇ ) and the structure of R. Along with each column temperature
• the purity of the obtained substance was 96.4% based on the gas chromatographic area percentage, and the gas chromatographic area percentage of diddecyl disulfide was 2.4%. Met.
• the purity of the obtained substance was 96.9% based on the gas chromatographic area percentage, and the gas chromatographic area percentage of didezynoresulphide was 2.3%. there were.
• Comparative Example 3 To a mixture of 0.69 g of 60% hydrogenated sodium and a mixture of dry tonoren, was added 1.46 g of a solution of azachin-opening pentane-2-on in toluene. The mixture was heated under reflux for 1 hour.
• reaction solution was washed with water and dried, and the solvent was distilled off under reduced pressure. Then, ethanol 100 ⁇ , water 10 and tributinolephosphine 0.12 g were added, and the mixture was further stirred at room temperature for 1 hour. Subsequently, ethyl acetate is added to the reaction mixture, washed with water, dried, and the solvent is distilled off. The residue is distilled to obtain [2- (decylthio) ethyl] aza-mouth pen. 2.75 g was obtained.
• the purity of the obtained substance was 92.1% based on the gas chromatographic area percentage, and did not show any residual impurities but did not detect any other impurities. Many were detected.
• a high-purity azacycloalkane derivative can be produced more easily and in a shorter time by treating with a reducing agent after completion of the reaction according to the present invention. This is as described above.
• a product having the same purity as that of the azacycloalenoline derivative synthesized according to the present invention is to be obtained by a conventional method, it is difficult to obtain a product by a chromatographic process. It is necessary to carry out distillation and purification after complicated operations such as recrystallization or the like, which requires a lot of time, processing equipment and a solvent for processing and purification.
• purification is easy because the amount of by-product dialkyl disulfide is extremely small, and for example, high purity azacyclo is obtained only by simple distillation purification. Lucan derivatives can be produced.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyrrole Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Steroid Compounds (AREA)
• Catalysts (AREA)

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Citations (2)

• 1990
  • 1990-10-31 JP JP2291876A patent/JPH07595B2/ja not_active Expired - Lifetime
• 1991
  • 1991-10-23 ES ES91918597T patent/ES2154632T3/es not_active Expired - Lifetime
  • 1991-10-23 AT AT91918597T patent/ATE199372T1/de not_active IP Right Cessation
  • 1991-10-23 WO PCT/JP1991/001451 patent/WO1992007827A1/ja active IP Right Grant
  • 1991-10-23 AU AU87624/91A patent/AU638613B2/en not_active Ceased
  • 1991-10-23 KR KR1019930701267A patent/KR960014349B1/ko not_active IP Right Cessation
  • 1991-10-23 CA CA002089880A patent/CA2089880C/en not_active Expired - Fee Related
  • 1991-10-23 DE DE69132547T patent/DE69132547T2/de not_active Expired - Lifetime
  • 1991-10-23 US US08/050,148 patent/US5371238A/en not_active Expired - Lifetime
  • 1991-10-23 EP EP91918597A patent/EP0555483B1/en not_active Expired - Lifetime
  • 1991-10-23 CN CN91108088A patent/CN1026320C/zh not_active Expired - Lifetime

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